The anti-obesity drug orlistat reveals anti-viral activity

Abstract

The administration of drugs to inhibit metabolic pathways not only reduces the risk of obesity-induced diseases in humans but may also hamper the replication of different viral pathogens. In order to investigate the value of the US Food and Drug Administration-approved anti-obesity drug orlistat in view of its anti-viral activity against different human-pathogenic viruses, several anti-viral studies, electron microscopy analyses as well as fatty acid uptake experiments were performed. The results indicate that administrations of non-cytotoxic concentrations of orlistat reduced the replication of coxsackievirus B3 (CVB3) in different cell types significantly. Moreover, orlistat revealed cell protective effects and modified the formation of multi-layered structures in CVB3-infected cells, which are necessary for viral replication. Lowering fatty acid uptake from the extracellular environment by phloretin administrations had only marginal impact on CVB3 replication. Finally, orlistat reduced also the replication of varicella-zoster virus moderately but had no significant influence on the replication of influenza A viruses. The data support further experiments into the value of orlistat as an inhibitor of the fatty acid synthase to develop new anti-viral compounds, which are based on the modulation of cellular metabolic pathways.

Inhibitors of VPS34 and lipid metabolism suppress SARS-CoV-2 replication

“…As in our study, flaviviruses were sensitive to relatively high concentrations of Orlistat and antiviral effects could be demonstrated when Orlistat was added to cells post-infection 17 . Virus inhibition has typically been demonstrated at relatively high concentrations of Orlistat, such as 100μM or higher for CVB3, and between 10μM and 84μM for DENV3, depending on the timepoint post-infection DENV3 replication was measured 17 , 19 , 49 . For DENV3, the effect of Orlistat appeared to be after the early stages of infection 18 .…”

“…Modulation of fatty acid metabolism has been shown to impact several viruses such as dengue virus, hepatitis C virus, and Old World alphaviruses 18,29,30 . Two well-described compounds that inhibit fatty acid metabolism are Orlistat and Triacsin C, both of which have been shown to have antiviral activity 19,30 . Orlistat is an FDA-approved drug that inhibits lipases and also fatty acid synthase (FASN), and Triacsin C inhibits long chain Acyl-CoA synthetases.…”

“…Inhibition of these enzymes inhibits HCV and rotavirus replication. More general inhibitors of fatty acid synthetase such as Orlistat, also decrease replication of several different viruses [17][18][19][20] .…”

Evaluation of the antiviral activity of orlistat (tetrahydrolipstatin) against dengue virus, Japanese encephalitis virus, Zika virus and chikungunya virus

“…Because high levels of fatty acid from lipid biosynthesis can promote the rapid growth and division of cancer cells, orlistat has additionally been evaluated for the therapy of a number of cancers including endometrial, prostate, breast, and colorectal cancers [20][21][22][23][24][25] . Orlistat has also been evaluated as an antiviral agent, and previous studies have evaluated the usefulness of orlistat as an antiviral agent for coxsackievirus B3 and varicella-zoster virus 26 .…”

Fatty acid synthase and stearoyl-CoA desaturase-1 are conserved druggable cofactors of Old World Alphavirus genome replication

“…Mainly, Orlistat, a derivative of lipstatin, approved by the FDA (Ballinger and Peikin, 2002), active against CHIKV and MAYV in our hands, displays antiviral activity against Coxsackievirus B3 (Ammer et al, 2015), HCV (Nasheri et al, 2013) and DENV (Tongluan et al, 2017). The wide spectrum antiviral properties of this anti-obesity drug suggests its possible repurposing for anti-infectious applications.…”